1247119-36-3

Example 6: Preparation of ethyl (S)-2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methylureido)-4-morpholino-substituted butanoate oxalate (Salt formula 2) 1. a stirred mixture of (R)-(+)-α-amino-gamma-butyrolactone hydrobromide (92 g) with dichloromethane (500 ml) was cooled to -5°C to -8°C. 2. Carbonyldiimidazole (92 g) was added in batches, followed by dropwise addition of triethylamine (45 g) under continuous stirring until the ingredients were fully reacted. 3. 2-isopropyl-4-[(methylamino)methyl]thiazole dihydrochloride (100 g) and triethylamine (92 g) were added slowly to the reaction mixture. 4. The reaction mixture was stirred at 20-25°C for 15 hours. 5. Water (200 ml) was added to separate the organic layer and the combined aqueous layer was back-extracted with dichloromethane (100 ml). 6. The organic layer was washed with 20% aqueous citric acid (40 g) followed by water (200 ml). 7. The organic layer was concentrated under reduced pressure at 38-40°C to give the crude product urea N-methyl-N-[[2-(1-methylethyl)-4-thiazolyl]methyl]-N'-[(3S)-tetrahydro-2-oxo-3-furanyl] (80 g). 8. Dissolve the above urea (100 g) in dichloromethane (500 ml), add ethanol (100 ml) and cool to 0-5 °C. 9. Slowly add trimethylmethylsilyl bromide (183g) dropwise, warm to 19-25°C and stir until the reaction is complete. 10. Cool to 0-5°C, slowly add morpholine (230 g) dropwise, warm to 19-25°C and stir for 17 hours. 11. The morpholine hydrobromide was removed by filtration and the filter cake was washed with dichloromethane. 12. The filtrate was washed with water and the combined organic layers were concentrated to dryness under vacuum to give a residue. 13. The residue was dissolved in acetone (500 ml) and a solution of oxalic acid dihydrate (60 g) in acetone (400 ml) was slowly added. 14. The slurry was refluxed for about 1 hour, cooled to 0-5°C, the product was filtered, rinsed with acetone (200 ml) and dried under vacuum at 40°C to give the target product as a white to off-white solid (122 g).

[1] Patent: WO2015/83066, 2015, A1. Location in patent: Page/Page column 14
[2] Patent: US2018/30043, 2018, A1. Location in patent: Paragraph 0169